Novel 2-alkyl-5-thiazole-carboxylic acid derivatives

ABSTRACT

WHEREIN R has the above-assigned meaning and R&#39;&#39;1 is a linear alkyl of 1 to 12 carbon atoms.   WHEREIN R is hydrogen, an alkali metal, ammonium, the monovalent residue of an organic amine base or a substituted or unsubstituted alkyl and R&#39;&#39; is a linear alkyl of 3 to 12 carbon atoms, and their preparation, and hypolipemiant compositions containing at least one 2-alkyl-5-thiazole carboxylic acid derivative of the formula   2-Alkyl-5-thiazole carboxylic acid derivatives of the formula

United States Patent [191 Clemnce et al.

[ May 6,1975

[ NOVEL Z-ALKYL-S-THlAZOLE-CARBOXYLIC ACID DERIVATIVES [75} Inventors:Francois Clemnce,

Rosny-sous-Bois; Odile Le Martret, Paris, both of France [73] Assignee:Roussel Uclaf, Paris, France [22] Filed: Jan. 9, 1974 [21] Appl. No.1431,881

Related US. Application Data [63] Continuation of Serv No, 244,909,April 17, l972, abandoned, which is a continuation-in-part of Ser, No.842,017, July l5, 1969, abandoned.

[56] References Cited UNITED STATES PATENTS 3,476,766 I 1/1969 Brown260/302 R OTHER PUBLICATIONS Geiger et al., Chem, Abstracts, 67:11413 w(1967).

Primary ExaminerRichard J. Gallagher Attorney, Agent, or Firm-Hammond &Littell [57] ABSTRACT 2-Alkyl-5-thiazole carboxylic acid derivatives ofthe wherein R is hydrogen, an alkali metal, ammonium, the monovalentresidue of an organic amine base or a substituted or unsubstituted alkyland R is a linear alkyl of 3 to 12 carbon atoms, and their preparation,and hypolipemiant compositions containing at least one 2alkyl-5-thiazolecarboxylic acid derivative of the formula I A 1- n wherein R has theabove-assigned meaning and R, is a linear alkyl of l to 12 carbon atoms.

17 Claims, N0 Drawings NOVEL 2-ALKYL-S-THIAZOLE-CARBOXYLIC ACIDDERIVATIVES REFERENCE TO A PRIOR APPLICATION This application is acontinuation of our copending U.S. Pat. Application Scr, No. 244,909,filed Apr. l7, 1972, now abandoned, which in turn was acontinuation-in-part of our copending US. Pat. Application Ser. No.842,017, filed July 15. I969, now abandoned.

OBJECTS OF THE INVENTION It is an object of the invention to providenovel 2- alkyLS-thiazole carboxylic acid derivatives of the aboveformula I.

It is another object of the invention to provide a novel process for thepreparation of the compounds of formula I.

It is a further object of the invention to provide novel hypolipemiantcompositions containing at least one 2- alkyl-S-thiazole carboxylic acidcompound of formula II.

It is an additional object of the invention to provide a novel method ofreducing the amount of sanguine lipids in warm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

DESCRIPTION OF THE INVENTION R S COOK wherein R is hydrogen. analkali-metal. ammonium, the monovalent residue of an organic amine baseor a substituted or unsubstituted alkyl, and R is a linear alkyl of 3 toII! carbon atoms.

The substituent R is preferably hydrogen, an alkalimetal atom, such assodium; ammonium; the salt of an organic amine base, for example, loweralkylammonium, such as methylammonium, di-lower alkylarnmonium, such asdiethylammonium, diisopropylam monium, tri'lower alkylammonium, such astriethylammonium, lower alkylolammonium, such as ethanolammonium,di-lower alkylolammonium, such as diisopropanolammonium, collidinium,morpholinium, piperidinium; alkyl having 1 to II) carbon atoms, such asmethyl, ethyl, decyl; the alkyl residue of an aryl aliphatic alcohol.the aliphatic residue of which contains 1 to 6 carbon atoms. forexample. phenylalkyl having I to 6 carbon atoms in the alkyl, where thephenyl can have substituents, such as alkyl having I to 6 carbon atoms,halogen and alkoxy having I to 6 carbon atoms, such phenylmethyl,phenylethyl, pchlorophenylethyl. p-methylphenylethyl,pmethoxyphenylethyl, phenoxyalkyl having l to 6 carbon atoms in thealkyl, where the phenoxy can have substituents such as alkyl having 1 to6 carbon atoms, halogen and alkoxy having 1 to 6 carbon atoms, such asphenoxyethyl, 2-(p-chlorophenoxyl-2,2 -dimethyl ethyl, pmethoxyphenoxyethyl; dialkylaminoalkyl hav ing 4 to 10 carbon atoms,such as diethylaminoethyl,

diethylaminopropyl. dipropylaminoethyl; alkylpolyol having 3 to II)carbon atoms such as a-glyceryl or B-glyceryl; the alkyl residue of analkylheterocyclic alcohol, the aliphatic residue of which contains l to6 carbon atoms, for example, furylalkyl having I to 6 carbon atoms inthe alkyl, such as a-furylethyl, thienylalkyl having 1 to 6 carbon atomsin the all-tyl, such as 3 thienylpropyl, pyridylalkyl having l to 6carbon atoms in the alkyl, such as N-pyridylethyl. ,B-pyridylethyl,theophyllinylalkyl having l to 6 carbon atoms in the alkyl, such as theester of 7-hydroxymethyltheophylline, morpholinylalky! having 1 to 6carbon atoms in the alkyl, such as B-morpholinylethyl; and the ketonidesof alkylpolyols having 3 to If) carbon atoms, such as the acetonide ofa-glyceryl.

Preferably, when R represents an ester of an alkanol or a substitutedalkanol, the same has the partial formulae n Zr| Il CH2] and m 2u R2wherein n is an integer from 0 to 9, m is an integer from 1 to 6 and Ris a member selected from the group consisting of alkylpolyol having 2to 4 carbon atoms, di-

lower alkylamino, a heterocyclic ring having 5 or 6 ring atoms and atleast one hetero atom selected from the group consisting of nitrogen,sulfur and oxygen and from 3 to 5 carbon atoms. theophyllinyl. phenyl,halo pheny], lower alkylphenyl and lower alkoxyphenyl, as well as theacid addition salts of those compounds containing amino nitrogen atomsin the substituted alkanol.

The novel hypolipemiant compositions of the invention contain at leastone Z-alltyLS-thiazolecarboxylic acid derivative of the formula II:

as diisopropylammonium 2-propyl-5- thiazolecarboxylate ethyl 2-propyl-5-thiazolecarboxylate N,N-diethylaminoethyl Z-propyl-S-thiazolecarboxylate and its chlorohydrate 2,3-isopropylidenedioxy-propyl2-propyl-5- thiazolecarboxylate phenylethylZ-propyl-fi-thiazolecarboxylate wglyceryl 2-propyl-5-thiazolecarboxylatemethyl Z-propyl-S-thiazolecarboxylate morpholinylethyl 2-propyl-5thiazolecarboxylate and its chlorohydrate tert. butylZ-propyl-S-thiazolecarboxylate benzyl 2-propyl-5-thiazolecarboxylatepyridylmethyl 2-propyl-5-thiazolecarboxylate.

One can likewise mention the a-glycerol or B-glycerol esters of2-methyl-, Z-ethylor Z-n-propyl-S thiazolecarboxylic acids, thediethylaminoethyl or di' ethylaminopropyl or dipropylaminoethyl estersof the same acids.

One can likewise mention as good representatives of this family theesters of B-pyridylmethanol or of pchlorophenoxydsobutanol or of 7hydroxymethyl theophylline with the same acids.

The novel process of the invention for the preparation of compounds offormula I comprises reacting an alkylthioamide, of formula:

wherein R is a linear alkyl of3 to 12 carbon atoms with a lower alkylZ-halogeno-3-oxo-propionate of formula wherein Hal is a halogen atomother than fluorine and R" is a lower alkyl radical, such as ethyl,saponifying or hydrolyzing the resultant lower alkyl ester of 2-alkyl-'thiazolecarboxylic acid to form a correspondingZ-alkyl-S-thiazolecarboxylic acid which may be, if desired, salified bythe action of an alkaline or organic base, or esterified by the actionof a substituted or unsubstituted alkanol of the formula ROH where R hasthe above-assigned values.

Preferably the alkyl 2-halogeno-3-oxo-propionate is ethyl2-chloro-S-oxo-propionate; the condensation between the alkyl-thioamideand the alkyl 2-halogeno-3- oxo-propionate is effected in an organicsolvent, such as an aromatic or cyclic hydrocarbon or an alkanol; thecondensation between the alkyl thioamidc and the alkyl2-halogeno-3-oxo-propionate is effected at reflux of the solvent; thesaponification of the alkyl ester of Zalkyl-S-thiozolecarboxylic acid iseffected by an alkaline agent such as an alkali metai hydroxide in alower alkanolic solvent; the salification of the Z-alkyl-S-thiazolecarboxylic acid is effected by the action of an alkali-metalbase, in an aqueous medium; the salifica tion of the2-alkyl-S-thiazolecarboxylic acid by the action of an organic base iseffected in an anhydrous or aqueous organic solvent. such as acetone orethanol; the esterification of the 2-alkyl S-thiazolecarboxylic acid iseffected by the action of an alkanol. in the presence of an acidcatalyst or by a diazoalkane.

The novel hypolipemiant compositions of the invention are comprised ofatleast one compound of formula ll and a major amount ofa pharmaceuticalcarrier. The compositions may be in the form of injectahle solutions orsupensions. tablets, coated tablets, cachets, cap

4 sules. granules. emulsions, syrups and suppositories prepared in theusual manner.

The novel compositions of the invention may include one or morecompounds of similar activity or synergistic effect, such as peripheralvasodilators, regulators of capillary permeability or antispasmodics.

The individual dose is 0.1 gm to 0.5 gm or from l mg/kg to 10 mg/kg,depending upon the method of administration.

The hypolipemiant compositions of the invention are useful for thetreatment of acute or chronic hyperlipidemis, of atheromatosis, ofhepatic or toxic steatosis, of lipid nephrosis and of circulatorytrouble such as arteritis or vascular spasms.

The novel method of the invention of reducing the amount of sanguinelipids in warm-blooded animals comprises administering to warm-bloodedanimals a safe and effective amount of at least one compound of formulall.

The said compounds may be administered orally, rec tally ortranscutaneously.

The usual useful daily dose is from 8 to 45 mg/kg depending upon themethod of administration.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE I 2Ethyl S-thiazolecarboxylic acid (R', CH CH and R H) Asolution of 26 gm of thiopropionamide in 100 cc of ethanol is mixed witha solution of 36.5 gm of ethyl 2-chloro 3-oxo-propionate in 50 cc ofethanol. The reaction mixture is left in contact overnight, then thealcohol is evaporated off. The residue is dissolved in ether, theethereal phase is washed with an aqueous 20% sodium carbonate solution,then with water. The oil obtained is distilled and the fraction comingoff at to C under a pressure of 0.5 mm is recovered. This fraction issaponified with an alcoholic solution of potassium hydroxide, thenacidified and recrystallized from toluene. 2-Ethyl-5-thiazolecarboxylicacid is obtained in the form of colorless crystals, soluble in ethanoland sodium hydroxide, insoluble in water, melting at 157C.

Analysis: C H NO S 157.19 Calculated: ("7: 45.34 H71 4.49 N /r 8.9l SW20.40 Found: 46.] 4.5 8.7 )0

Infrared Spectrum KBr: Bands at 3,1 15, 2,450, 1,850, L700, 1,280,1,160, 760 and 480 cm U.V. Spectrum ethanol: Max. at 250 mu The ethyl2-chloro-3-oxo-propionate is obtained according to the process describedby Elina, Majidson. CA. 45, 953le.

EXA MPLE ll 2 Propyl-5-thiazolecarboxylic acid (R CH- CH CH and R H)Operating in the same manner as in Example I, starting fromthiobutyramide. 2-propyl-5- thiazolecarboxylic acid is obtained in theform of colorless crystals, soluble in sodium hydroxide and alcohol,slightly soluble in ether. insoluble in water, melting at 137C.

Analysis: C H,.NO:S 171.22 Calculated: ("72 49.10 H% 5.30 N% 8.18 5%18.73 Found: 49.0 5.1 8.0 18.6

l.R. Spectrum KBr: Bands at 3,1 15, 2,480,1,850, 1,700,1,280, 1.150, 745and 480 cm U.V. Spectrum Ethanol: Max at 253 mp.

So far as one knows, this compound is not described in the literature.

EXAMPLE [I] Diisopropylamine 2-propy]-5-thiazolecarboxylate and R ca caca \CH(CH3)2 2 2 3) 4.45 Grams of 2-propyl 5thiazolecarboxylic acid(obtained in Example II) are dissolved in 120 cc of acetone and 2.62 gmof diisopropylamine are added. The solvent is evaporated off under lowpressure and the crystals thus obtained are recrystallized fromisopropyl ether. The diisopropylammonium 2-propyl-5- thiazolecarboxylateis obtained in the form of colorless crystals, soluble in water and inalcohol, melting at 120C (Yield: 90%).

Analysis: C H N O S 272141 Calculated: N% 10.28 5% 11.77 Found: 102611.79 11.75

So far as one knows this compound is not described in the literature.

EXAMPLE IV 2n-pentyI-S-thiazolecarboxylic acid Operating in the samemanner as in Example I starting from thiohexanoamide, 2-n-penty1-5-thiazolecarboxylic acid is obtained in the form of color less crystals,soluble in sodium hydroxide and alcohol, slightly soluble in ether,insoluble in water, melting at 90C (Yield: 45%).

Analysis: C H NO S 227.33 Calculated: N% 7.03 5% 16.10 Found: 6.99 7.04l6.l9 16.15

LR. Spectrum KBr:

Bands at 3,180, 2,480, 1,850, 1,690, 1,270, 1,150, 800 and 765 UV.Spectrum 4 Ethanol:

Max at 254 mp less crystals, soluble in sodium hydroxide and alcohol,insoluble in water, melting at 73C (Yield: 39%).

Analysis: C H NO S 241.34 Calculated: N% 6.56 5% 15.03 Found: 6.35 1499LR. Spectrum KBr:

Bands at 3,110, 2,480, 1,850, 1,680, 1,240, 1,150 and 755 U.V. SpectrumEthanol:

' Max. at 253 my So far as one knows, this compound is not described inthe literature.

EXAMPLE Vl 2-n-butyl-5thiazolecarboxylic acid Operating in the samemanner as in Example 1, starting from thiovaleramide, 2-n-butyl-5-thiazolecarboxylic acid is obtained in the form of colorless crystals,soluble in alcohol, chloroform and benzene, insoluble in water, meltingat 97C (Yield:

Analysis: c,.H,,No,s 135.24 Calculated: w 7.56 5% 17.31 Found: 7.52 7.4717.21 1720 LR. Spectrum KBr: Bands at 3,100, 2,500, 1,680, 1,270, 1,150and 745"" U.V. Spectrum Ethanol: Max. at 253 mp So far as one knows,this compound is not described in the literature.

EXAMPLE V11 2-n-undecyl-5-thiazolecarboxylic acid (RI (CH2)10CH3 and ROperating in the same manner as in Example I, starting fromthiolauramide, Z-n-undecyl-S- thiazolecarboxylic acid is obtained in theform of colorless crystals, soluble in alcohol and acetone, insoluble inwater, melting at 93C (Yield: 31%).

Analysis: C, -,H ,NO S 283.42 Calculated: N% 4.94 5% 11.31 Found: 4.92H.214

[.R. Spectrum KBr: Bands at 2,920, 2,500, 1,700, 1,250, 1,100 and 750U.V. Spectrum Ethanol: Max. at 245 mu So far as one knows. this compoundis not described in the literature.

The starting aliphatic thioamides are obtained by a procoess analogousto that described by Gilbert and Rumanowski. CA., 65. 20.0200.

EXAMPLE VIII Ethyl Z-propyl -thia2olecarboxylate 30 Grams ofZ-propyl-5-thia2olecarboxylic acid (obtained in Example II) is dissolvedin 4UU cc of ethanol. A stream of hydrochloric acid gas is passedthrough the solution for a period of four hours while maintaining thetemperature in the vicinity of25 to 30C. The solution is then maintainedovernight. Thereafter, the mix ture is evaporated to dryness. The oilyresidue is taken up in aqueous potassium carbonate solution. Thesolution is extracted with ether. The organic phase is separated andwashed with water until the wash waters are neutral. The organic phaseis then dried, decolorized with carbon black. filtered and evaporated todryness under vacuum. 33.1 Grams of ethyl Z-propyl-S- rawdiethylaminoethyl ester are thus recovered. The raw ester is taken up in100 cc of ether and 10 cc of water. The organic solution is washed witha 1071 aqueous potassium carbonate soltuion. The organic phase isseparated and washed with water. The combined aque ous phases are washedagain with ether. The combined ethereal phases are washed with water anddried over magnesium sulfate.

The ether is distilled off and 11.45 gm of the crudeN.N-diethylamino-ethyl IpropyLS-carboxylate is recovered in the form ofa liquid. By distillation. 9 gm of a fraction distilling at l l6 to [20Cunder 0.] mm of Hg is obtained. A new distillation furnishes 8 gm ofN.N-diethylamino-ethyl Z-propyI-S- thiazolecarboxylate distilling at Il8 119C under ().I mm of Hg.

PREPARATION OF THE CHLORHYDRATE 7.8 gm of the diethylaminoethyl esterare placed in 30 cc ofether and the stoichiometric amount of 2Nhydrochloric acid in ethanol is added. After evaporation of thesolvents, 8.8 gm of the chlorhydrate of N.N diethylamino-ethyl2'pr0pyl-5-carboxylate is obtained thiazolecarboxylate are recovered inthe form of a yelin the form of colorless crystals melting at l2 I-l22C. low oil, being a yield of 95%. For analysis, the chlorhydrate isrecrystallized from The ester is purified by fractional distillation31.2 ethyl acetate. The melting point remained unchanged. Grams ofa pureproduct distilling at l39- 140C under U.V. Spectra Ethanol; l6 mm of Hgwere recovered. Max. 260 mu Analysis: C,;.H.,;,N.,O,SCI 306.36Calculated: (/1 50.88 H'7I 7.55 cm ll.55 N0? 9.13 5% 10.45 Found: 51.07.4 l|.4 9.2 10.2

The ethyl-Z-propyl-S-thiazolecarboxylate occurs in The chlorhydrate ofN.Ndiethylamino-ethyl 2- the form of a liquid having an index ofrefraction propyl-5-thiazolecarboxylate occurs in the form ofcol- [N22.5 1,5025 (Yield: 89.5% orless crystals. soluble in water. ethanol.propylene glycol. acetone. and chloroform. slightly soluble in ethylacetate and benzene. and insoluble in ether. Amlwix C H N50 W926 So faras one knows, these products are not described Calculated: m 54.24 m 65?NG; 7.02 S I 16.09 in lhe lllcmlure- '1 Found 5-1.- 6.6 7.3 loll EXAMPLEX 2.3-lsopropylidenedioxy'propyl In TLC the product is homogeneous. l]-j hi l b So far as one knows. this product is not described in theliterature. (8 6x26 an d R CH CH CH I EXAMPLE IX 2 3 2 i 2N.N-diethylamino-ethyl 2-propyl-S-thiazolecarboxylate and itschlorohydrate CH CH "3 "3. (B' CH CH2CH andR I CH2CH2N\ cH2cH3 l0 Gramsof ethyl 2-propyl-5-thiazolecarboxylate (obtained in Example VIII) aredissolved in 66 gm of 7.01 Grams of 2-propyl-5-thiazolecarboxylic acid-is0pr0pylidenedioxy-propanol. 0.57 Grams of a (obtained in Example II)is placed in suspension in I50 50% suspension of sodium hydride inVaseline oil is cc ofanhydrous acetone. 3.96 Grams of potassium caraddedthereto. The solution obtained is heated to bonate is added thereto.then rapidly. under agitation. 70C for 2 hours while separating theethanol 8.27 gm of diethylaminoethyl chloride is added. The evolved.Next. 2.3-isopropylidenedioxy-propanol in exreaction mixture is thenrefluxed for a period of IO cess is evaporated under vacuum. Theamorphous resihours. 65 due is taken up in 700 cc of ether and cc ofwater.

The mixture is then cooled to room temperature; the mineral salts areremoved by filtration; then the ace tone is distilled off under vacuum.I29 Grams of the The ethereal phase is washed with water. separated.dried. passed through carbon black. filtered and evaporated. l3 Grams ofan oil is obtained. being a yield of 9l7r. The ester is purified byfraction distillation. The 2.3-isopropylidene dioxy-propyl 2-propyl-5-thiazolecarboxylate distills at 140C under 0.] mm of Hg. l().7 Grams ofpure ester is thus recovered (Yield: 75%

Calculated /1 54.7] H95 6.7 SQ [L33 Ni-i 4.9K)

Found: 55.0 (1.9 l L4 5.2

I.R. Spectra:

EXAMPLE Xl Phenylethyl 2-pr0pyl-5-thiazolecarboxylate (a' CH2CH2CH3 anda cn cH 6.84 Grams of 2-propyl-S-thiazolecarboxylic acid (described inExample ll) are placed in suspension in 45 cc of anhydrous ether. Over 3minutes, 6.07 gm of triethylamine in solution in l5 cc of acetone areadded thereto. A limpid solution is obtained. The solution is pouredthen into a solution of 5.42 gm of ethyl chloroformiate in 25 cc ofanhydrous acetone while maintaining the temperature ofthe reactionmedium between 6 and 8C over a period of minutes. The mixture is thenagitated for one hour at ambiant temperature and then filtered. 4.88Grams of phenylethanol in 45 cc of acetone are added over 5 minutes. Themixture is then agitated for 40 hours; then the solvents are distilledoff. 13 Grams of raw phenylethyl 2-propyl-5- thiazolecarboxylate is thusobtained.

The raw product is dissolved in 140 cc of ether and the etherealsoltuion is washed twice with 15 cc ofa 57! aqueous potassium carbonatesolution, then with water. The ethereal phase is next dried. treatedwith carbon black. filtered and evaporated to dryness. 9.52 Grams of aclear yellow oil are thus recovered.

The phenylethyl 2-propyl-5-thiazolecarboxylate is next rectified byfractional distillation under vacuum. 4.72 Grams of pure ester arerecovered between l40 to l50C under (H mm of Hg in the form ofa clearyellow liquid product. soluble in ether and acetone and in- U.V. SpectraEthanol:

Max 252 mp. E, 420 Index of refraction N 1.5495

So far as one knows, this product is not described in the literature.

EXAMPLE Xll a-glyceryl 2-propyl-5-thioazolecarboxylate (R' CH CH CH andR CH CHOHCH OH) The 2,3-isopropylidenedioxy-propyl 2-propyl-5-thiazolecarboxylate of Example X is subjected to acidic hydrolysis toremove the acetonide and a-glyceryl 2 propyl-5-thiazolecarboxylate isrecovered. having a melting point of 7lC (isopropylether) in a yield of62%.

EXAMPLE XIIl Methyl 2-propyl-5-thiazolecarboxylate (R CH CH CH and R CHFollowing the esterification process of Example Vlll. but utilizingmethanol. methyl 2-propyl-5 thiazolecarboxylate is recovered having aboiling point of 129C under 14 mm of Hg with a yield of 88%.

25 EXAMPLE XlV Morpholinylethyl Z-propyl-S-thiazolecarboxylate and itschlorohydrate (n' CH2CH2CH3 and a ca ca n o EXAM PLE XV Tert.-butyl2-propyl-5-thiazolecarboxylate ca (3' CHQCHQCH3 and a csg ng 3 Followingthe esterification process of Example VlIl, but utilizing tert.-butanol.tert.-butyl 2-propyl-5- thiazolecarboxylate is recovered having amelting point of 48C (hexane) with a yield of 4871.

EXAMPLE XVI Pyridylmethyl 2-propyl-5-thiazolecarboxylate I (R' CH2CH2CH3and R 011 11 Following the transesterification process of Example X. bututilizing pyridylrnethanol. pyridylmethyl 2- propyl5 thiazolecarboxylateis recovered.

EXAMPLE xvii Benzyl 2-propyl-5-thiazolecarboxylate (R' CH CH CH and R CHGHS) 8.5 grams Z-propyl--thiazolecarboxylic acid are dis solved underatmosphere of nitrogen into a mixture of 5.4 grams of benzyl alcohol and75 cc of tctrahydrofuran. After cooling to 0C a solution of 10.3 gramsof dicyclohexyl carbodiimide in 75 cc of tetrahydrofuran is added. Thenthe mixture is warmed to room temperature and left during 22 hours.

The precipitate is filtered and the filtrate evaporated to dryness. Theoily residue is extracted twice with ether. The organic solution iswashed with a per cent sodium carbonate solution then with water untilthe pH of the aqueous washings reaches a pH of 6.

The organic solution is dried on sodium sulfate, dried. decolorized withcharcoal. filtered and evaporated under reduced pressure.

The raw ester is then purified by chromatography on silica gel andelution with a mixture of ethyl acetate and cyclohexane; 4 grams ofbenzyl 2-propyl-5- thiazolecarboxylate are thus recovered.

The benzyl 2'propyl-5-thiazolecarboxylate is a yellow oil soluble inether and ethanol, insoluble in water. lts refraction index N l.5547.

Analysis c H Nso 261.33 Calculated: C r 64.33 H /i 5.73 N 5.36 S5; 12.26Found 64.3 5.5 5.5 12.1)

The various salts and esters of other 2-alkyl-5- thiazolecarboxylicacids can be produced following the processes of Examples lll and VlIlto XVI. using the acids of Examples 1 and 1V to VII.

PHARMACOLOGICAL DATA TABLE 1 lntraperitoneal Products Route Oral RouteImethyL5-thiazolecarhoxylic acid 2 gm/kg lethyl-5-thialolccarhoxylicacid 525 mgi'ltg 2 gm/kg Z-propyl-Sthizuolecarhoxylic acid 1.6M] mg/kg 2gm/kg 2. Determination of hypolipemiant activity:

The hypolipemiant activity has been determined on the rat according tothe technique of Jacobs et al, Proc. Soc. Exp. Biol. Med. [1965}, 119(4) pp. 1l17l 120.

Male rats of the Wistar strain weighing from 160 to 180 gm are not fedfor 24 hours. The products employed in a 5% suspension in gum arabicsolution in water. are administered through an oesophagial probe atdoses of 20, 40 and mg/kg. Four hours after ingestion of the product,some blood is withdrawn on which a determination of the triglycerides iscarried out.

The principle of the determination is as follows:

The serum lipids are extracted with petroleum ether in the presence ofethanol. The lipidic solution is treated several times with 87% ethanol.A solution is thus obtained, the upper part of which contains theglycerides and the lower part, the phospholipids.

The weight of the glycerides is determined by determination ofglycerolby per-iodic acid oxidation and determination of the formaldehyde withchromotropic acid.

The results obtained are summarized in the following Table ll.

TABLE II Percentage of Reduction by Comparison With Products DosesControls Z-methyl-5-thiazole carboxylic acid 20 mg/kg 40Z-ethyl-S-thiazolecarboxylic acid 20 mg/kg 50Z-propyl-5-thiazolecarhoxylic acid 21] mg/kg 50 tained.

TABLE III Period of Doses Induction Duration Inten- Products mg/kg min.min. sity Z-methyl-S-thiazole [U 5 3O +l+- carhoxylic acid 20 3 32 -+H5O 3 3S Z-ethyl-S-thiazole 50 6-8 50 carhoxylic acid I00 6-7 60 ++i-2propyI-5-lhiazole 5t) 13 30 carboxylic acid I00 10 32 These resultsshow that the products studied possess a marked peripheral vasodilatoryactivity.

COM PARlSON TESTS The following tests with ethyl 2-n-propylthiazole-4-carboxylate (described by, Geiger et al, C.A.. 67, 11413) wereconducted.

TEST DATA A. Determination of hypolipemiant activity:

The hypolipemiant activity was determined on the rat using the techniqueof Jacobs et al (Proc. Soc. Exp. Biol. Med.,'[1965]. 119 [4], pp.1117-1120). Male rats of the Wistar strain weighing from I60 to gm werenot fed for 24 hours. The product employed in a suspension in gum arabicsolution in water, was administered orally through an oesophagial probeat doses of and 80 mg/kg. Four hours after ingestion of the product,some blood was withdrawn and a determination of the triglyceridestherein was made.

The principle of the determination is as follows:

The serum lipids are extracted with petroleum ether in the presence ofethanol and the lipidic solution was treated several times with 87%ethanol to obtain a solution, the upper part of which contained theglycerides and the lower part the phospholipids. The weight of theglycerides by determination of glycerol by per-iodic acid oxidation anddetermination of the formaldehyde with chromotropic acid is estimated.There was no action on the triglycerides by ethyl 2-n-propyl-thiazole-4-carboxylate at either dose.

B. Peripheral vasodilatory effect:

The peripheral vasodilatory effect was investigated on guinea pigs withnon-pigmented ears by the appearance of the reddening of the ear. Theanimals were starved and the product was administered intraperitoneallyat a dose of 100 mg/kg. The time of appearance of a reddening of theears, the duration ofthis reddening and its intensity being recordedsubjectively from 0 -H+- is determined.

The test showed no vasodilatory activity for the said ester, ethyl2-n-propyl-thiazole-4-carboxylate, at this dosage.

C. Hypothermic activity:

The hypothermic activity was determined on guinea pigs by administeringthe test compound, ethyl 2-n propyl-thiazole-4-carboxylate,intraperitoneally at a dose of 100 mg/kg. The body temperature of theguinea pigs was determined one-half hour before the administration ofthe test compound and then 1, 2 and 3 hours after the saidadministration. There was no hypothermic activity at the dose of lOOmg/kg.

D. Determination of the acute toxicity:

The acute toxicity was determined on batches of ten mice weighing from18 to 22 gm. Ethyl 2-npropylthiazole-4-carboxylate was administered insuspension in gum arabic solution in water, at increasing doses by theintraperitoneal route. The animals were kept under observation for lweek. The average lethal dose (LD was determined graphically by themethod of Dragstedt and Lang. The DL in this test fell between l000 and1500 mg/kg.

It can be concluded from the above comparison test that ethyl2-n-propyl-thiazole-4-carboxylate has no hypothermic or vasodilatoryactivity at an intraperitoneal dose of 100 mg/kg and no hypolipemiantactivity at an oral administration of 20 and 80 mg/kg, compared with theproducts ofthe invention as reported in Tables I, II and Ill.

The preceding specific embodiments are illustrative of the practice ofthe invention. It is to be understood, however, that other expedientsknown to those skilled in the art or disclosed herein, may be employedwithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. 2-Alkyl-5-thiazole carboxylic acid derivative of the formula whereinR is a member selected from the group consisting of hydrogen, an alkalimetal, triethylammonium, diisopropylammonium, diethylammonium,ethanolammonium, collidinium, morpholinium, piperidinium, and alkylhaving 1 to [0 carbon atoms and R is a linear alkyl of 3 to l2 carbonatoms.

2. A compound of claim 1 wherein R is hydrogen and R is n-propyl.

3. A compound ofclaim 1 wherein R is hydrogen and R is n-butyl.

4. A compound of claim 1 wherein R is hydrogen and R is n-pentyl.

5. A compound of claim 1 wherein R is hydrogen and R is n-hexyl.

6. The compound of claim 1 wherein R is hydrogen and R is n-undecyl.

7. A compound of claim 1 wherein R is diisopropylammonium and R isn-propyl.

8. A compound of claim 1 wherein R is methyl and R is n-propyl.

9. A compound of claim I wherein R is tert.-butyl and R is n-propyl.

10. A compound of claim 1 wherein R is n-propy].

11. A compound of claim 1 wherein R is hydrogen.

12. 2-Alkyl-5-thiazole carboxylic acid derivatives of the formula N R" scoon wherein R is a member selected from the group consisting ofhydrogen, alkali metal, triethylammonium, diisopropylammonium,diethylammonium, ethanolammonium, collidinium, morpholinium,piperidinium, alkyl of 1 to 10 carbon atoms, benzyl, the alkyl residueof an alkylheterocyclic alcohol the alkyl residue of which contains 1 to6 carbon atoms and of which the heterocyclic residue is selected fromthe group consistint of furyl, thienyl and pyridyl, a-glyceryl,B-glyceryl. diethylaminoethyl, diethylaminopropyl and dipropylaminoethyland R is a linear alkyl of3 to 12 carbon atoms.

13. A compound of claim 12 wherein R is 2,3- isopropylidenedioxy-propyland R is n-propylv 14. A compound of claim 12 wherein R is a-glyceryland R is n-propyl.

15. A compound of claim 12 wherein R is morpholinylethyl and R isn-propyl.

16. A compound of claim 12 wherein R is pyridylmethyl and R is n-propyl.

17. A compound of claim 12 wherein R is benzyl and R is n-propyl.

1. 2-ALKYL-5-THIAZOLE CARBOXYLIC ACID DERIVATIVE OF THE FORMULA
 2. Acompound of claim 1 wherein R is hydrogen and R'' is n-propyl.
 3. Acompound of claim 1 wherein R is hydrogen and R'' is n-butyl.
 4. Acompound of claim 1 wherein R is hydrogen and R'' is n-pentyl.
 5. Acompound of claim 1 wherein R is hydrogen and R'' is n-hexyl.
 6. Thecompound of claim 1 wherein R is hydrogen and R'' is n-undecyl.
 7. Acompound of claim 1 wherein R is diisopropylammonium and R'' isn-propyl.
 8. A compound of claim 1 wherein R is methyl and R'' isn-propyl.
 9. A compound of claim 1 wherein R is tert.-butyl and R'' isn-propyl.
 10. A compound of claim 1 wherein R'' is n-propyl.
 11. Acompound of claim 1 wherein R is hydrogen.
 13. A compound of claim 12wherein R is 2,3-isopropylidenedioxy-propyl and R'' is n-propyl.
 14. Acompound of claim 12 wherein R is Alpha -glyceryl and R'' is n-propyl.15. A compound of claim 12 wherein R is morpholinylethyl and R'' isn-propyl.
 16. A compound of claim 12 wherein R is pyridylmethyl and R''is n-propyl.
 17. A compound of claim 12 wherein R is benzyl and R'' isn-propyl.